XMRV is a gammaretrovirus first identified in prostate tissues of Prostate Cancer (PC) patients and later in the blood cells of patients with Chronic Fatigue Syndrome (CFS). Although XMRV is thought to use XPR1 for cell entry, it infects A549 cells that do not express XPR1, suggesting usage of other receptors or co-receptors.

Methods

To study the usage of different receptors and co- receptors that could play a role in XMRV infection of lymphoid cells and GHOST (GFP- Human osteosarcoma) cells expressing CD4 along with different chemokine receptors including CCR1, CCR2, etc., were infected with XMRV. Culture supernatants and cells were tested for XMRV replication using real time quantitative PCR.
Results

Infection and replication of XMRV was seen in a variety of GHOST cells, LNCaP, DU145, A549 and Caski cell lines. The levels of XMRV replication varied in different cell lines showing differential replication in different cell lines. However, replication in A549 which lacks XPR1 expression was relatively higher than DU145 but lower than, LNCaP. XMRV replication varied in GHOST cell lines expressing CD4 and each of the co- receptors CCR1 - CCR8 and Bob. There was significant replication of XMRV in CCR3 and Bonzo although it is much lower when compared to DU145, A549 and LNCaP.

Conclusion

XMRV replication was observed in GHOST cells that express CD4, and each of the chemokine receptors ranging from CCR1- CCR8 and Bob suggesting that infectivity in hematopoietic cells could be mediated by use of these receptors.

I thought it was interesting that cells which lack the XPR1 receptor could be infected, since they thought that was the means of infection. But I'm not clear on how you mean that is further evidence that it's a human virus?

I'm glad to know the FDA Laboratory of Molecular Virology is continuing to research XMRV, or at least to publish the studies they've done.

Hi, an alternate mode of cell entry has been known to exist for some time now for XMRV, but we didn't know which receptor it was. T Helper cells (CD4) are also targets for HIV. I wonder if this explains a Th2 cytokine shift, or if other factors are involved?

Natural Killer T Cells (which are different from Natural Killer Cells) can also have a CD4 receptor (a subtype). They also express the NK cell marker as NK cells do. I wonder if this is related to the NK cell subtype findings made in the Bond University study?

I thought it was interesting that cells which lack the XPR1 receptor could be infected, since they thought that was the means of infection. But I'm not clear on how you mean that is further evidence that it's a human virus?

I'm glad to know the FDA Laboratory of Molecular Virology is continuing to research XMRV, or at least to publish the studies they've done.

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Sorry to confuse, I was a bit clumsy with my syntax. I meant: 'further evidence that it can infect humans'.

Not evidence that XMRV can 'infect humans' in the sense of causing disease, let alone become communicable. That XMRV can find a home in (some) human cells is not in doubt, what has yet to be established is what this means outside of the test tube; the Macaque study suggests not very much, give a monkey an enormous volume of virus and what happens - nothing, not the slightest sign of illness. XMRV might have all sorts of nasty capabilities but so far there's zero evidence of it causing disease.

Not evidence that XMRV can 'infect humans' in the sense of causing disease, let alone become communicable. That XMRV can find a home in (some) human cells is not in doubt, what has yet to be established is what this means outside of the test tube; the Macaque study suggests not very much, give a monkey an enormous volume of virus and what happens - nothing, not the slightest sign of illness. XMRV might have all sorts of nasty capabilities but so far there's zero evidence of it causing disease.

IVI

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As for the macaque study: the monkeys might not have shown signs of illness, but that doesn't say much, does it? It could be that XMRV takes years to cause disease, while they studied these monkeys only for a short period. They might also react differently as humans to this virus. It could also be it only causes disease in animals or persons with a specific genetic defect. Maybe a coinfection is needed...

(If you take the early days of HIV for example, when they knew almost nothing about it yet and it wasn't even called HIV yet. If you would then have injected HIV in some humans and studied them for a few months, your conclusion could have been that they did not react to it or just got the flu from it. The real damage in these humans would only have presented itself later, when the research for that particular paper was already finished).

What I remember from the macaque study is that the virus quickly left the blood or was eliminated, but it was again found in the blood when the monkeys were injected with something (to stimulate their immune system if I remember correctly?). Which could mean the virus quickly enters tissue. There's evidence for that from both the macaque and cancer studies.

So to me everything is still possible... XMRV could really be contamination (which I personally believe to be highly unlikely), it could be causing several very serious diseases or anything in between.

What annoys me is that many researchers are trying to close the book on XMRV. I think it's far too premature to do that. MLV's and XMRV might be a healthcare disaster that has been plaguing us for decades... scientists should get to the bottom of this. And the bottom has not been reached. I even have the feeling they have barely scratched the surface.

Not evidence that XMRV can 'infect humans' in the sense of causing disease, let alone become communicable. That XMRV can find a home in (some) human cells is not in doubt, what has yet to be established is what this means outside of the test tube; the Macaque study suggests not very much, give a monkey an enormous volume of virus and what happens - nothing, not the slightest sign of illness. XMRV might have all sorts of nasty capabilities but so far there's zero evidence of it causing disease.

IVI

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No not proof, just evidence. When you add evidence to other evidence you can build your proof. The macaque study is another good piece of evidence. The salient point of the study for us was the finding that the virus did initially replicate rapidly inside the macaques. The study did not prove or disprove infectivity or disease, or whether the disease was still present in hold out areas. Not sure why you brought up the macaque study, but thanks for the reminder.

So what if the macaques did not show signs of disease; nor do patients with HIV, until much later. So XMRV acts like a retrovirus, surprise, surprise.

So what if the macaques did not show signs of disease; nor do patients with HIV, until much later. So XMRV acts like a retrovirus, surprise, surprise.

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Wrong - HIV has a demonstrable early symptomatic stage; even in the so called asymptomatic second stage there are identifiable processes of infection, all of this follows exposure to tiny volumes of virus. In the macaques, exposure was to levels of virus never found outside of a test tube, yet not a single disease process could be identified.

Wrong - HIV has a demonstrable early symptomatic stage; even in the so called asymptomatic second stage there are identifiable processes of infection, all of this follows exposure to tiny volumes of virus. In the macaques, exposure was to levels of virus never found outside of a test tube, yet not a single disease process could be identified.
IVI

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Not quite. If you read what you linked to it says "This stage of infection lasts for a few weeks and is often accompanied by a short flu-like illness." So, I think what you meant was "a sometimes demonstrable" symptomatic stage.

Also of note from your link is that "there is a large amount of HIV in the peripheral blood and the immune system begins to respond." Any primary stage symptoms are likely a result of this immune activation due to large quantities of free virus in the blood. The macaque studies showed that the virus quickly clears from the blood and retreats to tissue reservoirs. Would an identical immediate immune response be expected from such different conditions? In fact, if XMRV is (co-)causative of ME, the disease course would suggest that (barring triggering events) much of the effect is due to long-term virus pathology and not short-term inflammation/immune activation. Again, would not similar effects be plausible, if not expected, in macaques.

Furthermore, let's not overlook the fact that you are deriving speculative conclusions from comparing not just apples (HIV) to oranges (XMRV) but apple jelly (HIV in humans) to orange juice (XMRV in macaques).

Not quite. If you read what you linked to it says "This stage of infection lasts for a few weeks and is often accompanied by a short flu-like illness." So, I think what you meant was "a sometimes demonstrable" symptomatic stage.

Also of note from your link is that "there is a large amount of HIV in the peripheral blood and the immune system begins to respond." Any primary stage symptoms are likely a result of this immune activation due to large quantities of free virus in the blood. The macaque studies showed that the virus quickly clears from the blood and retreats to tissue reservoirs. Would an identical immediate immune response be expected from such different conditions? In fact, if XMRV is (co-)causative of ME, the disease course would suggest that (barring triggering events) much of the effect is due to long-term virus pathology and not short-term inflammation/immune activation. Again, would not similar effects be plausible, if not expected, in macaques. Furthermore, let's not overlook the fact that you are deriving speculative conclusions from comparing not just apples (HIV) to oranges (XMRV) but apple jelly (HIV in humans) to orange juice (XMRV in macaques).

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Not my comparison but Rusty's - I see no reason why XMRV should behave like HIV. But are you seriously saying that because the Macaques didn't say "hey Doc, I've got a bit of headache, I think I could be a bit ill" - that the researchers 'missed' a 'symptomatic' stage of XMRV infection ? They necropsied everyone of the animals - no disease process present, absolutely nothing, and if as Rusty argued that XMRV is like HIV, then even in an 'asymptomatic' phase there should have been clinically identifiable disease processes taking place. Just because some humans don't notice getting sick with HIV infection doesn't mean (thank goodness) the illness isn't identifiable in its 'asymptomatic' phase. Of course one can endlessly re-draw the parametres to describe an illness that is undetectable, that only becomes apparent under exceptional circumstance and is otherwise mysterious, but one can only go so far from physical evidence before that narrative ceases to be a valid hypothesis and becomes science fiction.

As for the macaque study: the monkeys might not have shown signs of illness, but that doesn't say much, does it? It could be that XMRV takes years to cause disease, while they studied these monkeys only for a short period. They might also react differently as humans to this virus. It could also be it only causes disease in animals or persons with a specific genetic defect. Maybe a coinfection is needed...

(If you take the early days of HIV for example, when they knew almost nothing about it yet and it wasn't even called HIV yet. If you would then have injected HIV in some humans and studied them for a few months, your conclusion could have been that they did not react to it or just got the flu from it. The real damage in these humans would only have presented itself later, when the research for that particular paper was already finished).

What I remember from the macaque study is that the virus quickly left the blood or was eliminated, but it was again found in the blood when the monkeys were injected with something (to stimulate their immune system if I remember correctly?). Which could mean the virus quickly enters tissue. There's evidence for that from both the macaque and cancer studies.

So to me everything is still possible... XMRV could really be contamination (which I personally believe to be highly unlikely), it could be causing several very serious diseases or anything in between.

What annoys me is that many researchers are trying to close the book on XMRV. I think it's far too premature to do that. MLV's and XMRV might be a healthcare disaster that has been plaguing us for decades... scientists should get to the bottom of this. And the bottom has not been reached. I even have the feeling they have barely scratched the surface.

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Hi Jemal,

I think XMRV being a contamination is out of the question, that was clearly said during the retrovirus conference here in Belgium. It has been confirmed by a researcher/organiser of that conference to me. She literally said: XMRV is a REAL virus. What yet has to be proven is:

- does it infect humans
- does it cause disease

I don't know why researchers want to close the book on XMRV/*MLV, but in the course of my illness, I learned that doctors and also researchers are part of the society we live in, and some of them are just not honoust, others are not integer as you would expect, some are even criminal.

Furthermore, let's not overlook the fact that you are deriving speculative conclusions from comparing not just apples (HIV) to oranges (XMRV) but apple jelly (HIV in humans) to orange juice (XMRV in macaques).

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That's correct. XMRV -they say- can be compared to HTLV, a virus that causes disease maybe 30 or 40 years later. Some(small minority of) people even don't get sick at all, when infected. You have that with HIV also, which are called the 'elite controllers'.
Until recently, they even didn't know HOW HTLV was causing immune deficiency, they thought that HTLV was just watching television in the cell. Which is not the case of course. The BIG difference between HTLV and XMRV is, that HTLV has accessory genes, which XMRV doesn't obviously have. That's one of the reasons it is called a 'simple' retrovirus, most likely. HTLV creates harmful proteines by means of those genes, and immune deficiency. XMRV most likely causes immune deficiency through it's envelope. Other retroviruses does that too. And, research is still in it's early phases, perhaps XMRV does have accessory genes, which is bad news of course.

Personally, I think XMRV needs co-infections, and the sum of the infections + genetics equals ME, or Lupus or... or... or...
Please correct me if I'm wrong, because I'm no retrovirologist, I just gained the knowledge by reading about it.

I think XMRV being a contamination is out of the question, that was clearly said during the retrovirus conference here in Belgium. It has been confirmed by a researcher/organiser of that conference to me. She literally said: XMRV is a REAL virus. What yet has to be proven is:

- does it infect humans
- does it cause disease

I don't know why researchers want to close the book on XMRV/*MLV, but in the course of my illness, I learned that doctors and also researchers are part of the society we live in, and some of them are just not honoust, others are not integer as you would expect, some are even criminal.

Take care,
OS.

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Hi Overstressed,

I think we mean the same thing. The contamination argument has shifted, they now no longer question if this is a real virus, but they question if it really infects humans. They are basically saying samples have been contaminated in laboratories with a virus that should not be found outside the laboratory. This is what they call contamination now and this is what I meant when I talked about contamination. I certainly don't question if this is a real virus and I find it highly unlikely this virus can only be found inside the laboratory. That is what the contaminists are claiming now though and they are also gathering evidence that even if XMRV came into contact with humans, it would be quickly eliminated by our defences. I don't buy that either.

I will probably only buy the contamination argument when laboratories like the WPI make a statement that a virus contaminated their samples and that is not likely to happen soon...

I think we mean the same thing. The contamination argument has shifted, they now no longer question if this is a real virus, but they question if it really infects humans. They are basically saying samples have been contaminated in laboratories with a virus that should not be found outside the laboratory. This is what they call contamination now and this is what I meant when I talked about contamination. I certainly don't question if this is a real virus and I find it highly unlikely this virus can only be found inside the laboratory. That is what the contaminists are claiming now though and they are also gathering evidence that even if XMRV came into contact with humans, it would be quickly eliminated by our defences. I don't buy that either.

I will probably only buy the contamination argument when laboratories like the WPI make a statement that a virus contaminated their samples and that is not likely to happen soon...

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Yes, we mean the same thing, you're right. To me it's no coincidence that XMRV quickly disappears into tissue, and on the other hand we have diseases that are called 'connective tissue' disorders... But, in the scientific world it's: if you can't prove it, it doesn't exist...

But, in the scientific world it's: if you can't prove it, it doesn't exist... OS.

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That is not how science is conducted, 'proof' is not part of the scientific process and hasn't been for the best part of four decades since the widespread acceptance of Karl Popper's philosophical assessment of science .

KP: "but those who uphold it dogmatically [a system] . . . are adopting the very reverse of that critical attitude which in my view is the proper one for the scientist. In point of fact, no conclusive disproof of a theory can ever be produced; . . . If you insist on strict proof (or strict disproof) in the empirical sciences, you will never benefit from experience, and never learn from it how wrong you are."

If you are so disatisfied with science, why are you concerned with what scientific research produces - it can never satisfy your requirements so why bother with it ? Although if you are going to express your disatisfaction, you might at least do so based on what science is rather than relying on false presentations.

IVI, neither in Onlamoon et al nor in this thread has anyone stated that the macaque study provided anything more than clues into potential pathogenesis that align with a number of other research observations.

Rather, it is you who is trying to twist and pervert the macaque study to support your implied "absence of (conclusive) evidence for pathogenesis equals no pathogenesis" argument.

The fact that the macaques did not show acute clinical symptoms of immune activation doesn't mean much, especially since the authors did demonstrate actual immune activation through various laboratory tests. HTLV rarely has a clinically acute phase.

You also state that "not a single disease process could be identified" despite ample laboratory evidence that demonstrated productive XMRV infection and immune-induced reactivation. Only if you narrowly and artificially define "disease process" as structural tissue damage could your assertion even begin to hold true. Even then, this (medium-term) lack of tissue necrosis doesn't begin to rule out a pathogenic role. In fact, HIV by itself (i.e. in the absence of opportunistic infections) induces pathology primarily through a long-term, kinetic reduction of CD4+ levels, which is probably not something that would show up on a 9-month necropsy. Would you therefore contend that there is "zero evidence of [HIV] causing disease"?

That is not how science is conducted, 'proof' is not part of the scientific process and hasn't been for the best part of four decades since the widespread acceptance of Karl Popper's philosophical assessment of science .

KP: "but those who uphold it dogmatically [a system] . . . are adopting the very reverse of that critical attitude which in my view is the proper one for the scientist. In point of fact, no conclusive disproof of a theory can ever be produced; . . . If you insist on strict proof (or strict disproof) in the empirical sciences, you will never benefit from experience, and never learn from it how wrong you are."

If you are so disatisfied with science, why are you concerned with what scientific research produces - it can never satisfy your requirements so why bother with it ? Although if you are going to express your disatisfaction, you might at least do so based on what science is rather than relying on false presentations.

IVI

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I think you've misunderstood or misconstrued Overstressed. I think he/she was making a rather astute (though oft-observed) indictment of modern science, in particular as it has handled the WPI's discovery. There is a scientific orthodoxy, it seems, and any discovery that runs counter to it is met with hostility disguised as "scientific skepticism." It could be deemed both ironic and illustrative that you quote Popper and lecture on "what science is" in the same thread in which you have engaged in logically unsound arguments against XMRV pathogenesis.

This orthodoxy is readily apparent by simply witnessing that, since the WPI discovery almost 2 years ago, the vast majority of effort and money from the scientific community has been spent trying to actively "disprove" and "discredit" their work (attempts which should not be mistaken with "falsifying an experimental hypothesis", which forms the foundation of real science).

This orthodoxy can be observed in the insistence by you and others that, because a single preliminary animal-model study didn't fully elucidate XMRV pathogenesis, that we should pack up and go home and get back to studying things we already largely understand. Where is the curiosity and inquisitiveness and thirst for knowledge that supposedly imbues these scientists? Instead we get arrogant speculation dressed up to look like research.

This orthodoxy shines through in claims that the process of novel discovery -- a naturally ill-defined, infrequently-trodden path -- amounts to "endlessly re-draw[ing] the parametres." What parameters? And why shouldn't they change, especially if they are defined by the very orthodoxy being challenged? How is it anything approaching reasonable to insist that scientists know everything about their discovery while they are discovering it? Joseph Heller would have bowed before the majesty of this catch-22.

IVI, neither in Onlamoon et al nor in this thread has anyone stated that the macaque study provided anything more than clues into potential pathogenesis that align with a number of other research observations.

Rather, it is you who is trying to twist and pervert the macaque study to support your implied "absence of (conclusive) evidence for pathogenesis equals no pathogenesis" argument.

The fact that the macaques did not show acute clinical symptoms of immune activation doesn't mean much, especially since the authors did demonstrate actual immune activation through various laboratory tests. HTLV rarely has a clinically acute phase.

You also state that "not a single disease process could be identified" despite ample laboratory evidence that demonstrated productive XMRV infection and immune-induced reactivation. Only if you narrowly and artificially define "disease process" as structural tissue damage could your assertion even begin to hold true. Even then, this (medium-term) lack of tissue necrosis doesn't begin to rule out a pathogenic role. In fact, HIV by itself (i.e. in the absence of opportunistic infections) induces pathology primarily through a long-term, kinetic reduction of CD4+ levels, which is probably not something that would show up on a 9-month necropsy. Would you therefore contend that there is "zero evidence of [HIV] causing disease"?

I think you've misunderstood or misconstrued Overstressed. I think he/she was making a rather astute (though oft-observed) indictment of modern science, in particular as it has handled the WPI's discovery. There is a scientific orthodoxy, it seems, and any discovery that runs counter to it is met with hostility disguised as "scientific skepticism." It could be deemed both ironic and illustrative that you quote Popper and lecture on "what science is" in the same thread in which you have engaged in logically unsound arguments against XMRV pathogenesis.

This orthodoxy is readily apparent by simply witnessing that, since the WPI discovery almost 2 years ago, the vast majority of effort and money from the scientific community has been spent trying to actively "disprove" and "discredit" their work (attempts which should not be mistaken with "falsifying an experimental hypothesis", which forms the foundation of real science).

This orthodoxy can be observed in the insistence by you and others that, because a single preliminary animal-model study didn't fully elucidate XMRV pathogenesis, that we should pack up and go home and get back to studying things we already largely understand. Where is the curiosity and inquisitiveness and thirst for knowledge that supposedly imbues these scientists? Instead we get arrogant speculation dressed up to look like research.

This orthodoxy shines through in claims that the process of novel discovery -- a naturally ill-defined, infrequently-trodden path -- amounts to "endlessly re-draw[ing] the parametres." What parameters? And why shouldn't they change, especially if they are defined by the very orthodoxy being challenged? How is it anything approaching reasonable to insist that scientists know everything about their discovery while they are discovering it? Joseph Heller would have bowed before the majesty of this catch-22.

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Well said, Just too many unknowns at this point to say why the macaques, showed little evidence of illness. to assume thats because xmrv does not can not produce illness, is not only premature, but quite frankly rather silly, it certainly does appear such observations in the macaques are used to bolster a viewpoint. on decidedly shaky ground. Ive always found it fascinating for example that the virus seemed to infect the prostate quite readily. When infact we are being told by some reaearchers xmrv is in no way linked to prostate cancer. Switzer says this even though he found the virus had infected a couple or so patients, in hes largly negative Prostate cancer xmrv study. It could of course all be just coincendence, as the virus does infect other organs in the macaques, but that would be expected. None the less, a postate infection should at the very least be viewed as interesting, if not suspiciouse.

Hi, I agree with IVI on one major point - none of the studies proves anything. They are evidence, but that evidence has to be assessed in the context of the study methodology and in the context of the other evidence.

What I think that IVI does not get is that, for many of us and that includes me, we are discussing an hypothesis, exploring where it may lead. I don't believe in the XMRV hypothesis, just as I don't believe that XMRV is irrelevant. I am interested in the facts, and whether or not those facts can help us find treatments.

For me there are now two major hypotheses, both of which I am interested in:

1. XMRV or a similar virus is causal. Even if XMRV is not the cause, that does not rule out similar or hybrid viruses. It is even possible that it is another retrovirus entirely, and the MLVs are indeed irrelevant, or that some subset of viral combinations might induce ME, including herpes or coxsackie family viruses.

2. XMRV or other factors are just triggers for an underlying immune dysfunction. That would make ME a variant autoimmune disease.

Of course there will be risk factors. I regard many of the other issues discussed in the research, such as kindling, NO/ONOO and methylation issues to be risk factors. I also regard sub-clinical haemochromotosis as a risk factor, which the CDC discussed in the 90s. How many risk factors are there? I don't know. The importance of risk factors can indirectly be assessed by prevalence, but this is limited by being post-ME prevalence, we don't know how important they are in a pre-disease setting. Top of my list is oxidative stress, followed by methylation, followed by over-training. Haemochromatosis is a form of oxidative stress in this context.

The other thing is, I have almost no problems with almost any of the studies on XMRV, either pro- or anti-XMRV. That doesn't mean I wont analyze them or express a view point, just that I consider every study interesting on its own terms. Those terms include the limitations of the methodology used, including post result analysis methods.

Where I do have a problem is the activism (yes, I am using that word) that goes with the anti-XMRV studies. Whereas for a scientific audience these studies are very careful to present reasoned outcomes, either by intent or by accident the media releases have been extremely hyperbolic along the lines of "XMRV research is dead" or "XMRV is just a contaminant" without much regard to the underlying evidence. It is the politics of the scientists and those who just think they are scientists that I object to. Even if the press releases and media interviews have "accidentally" given the wrong impression, this is still objectionable because nobody has gone back to correct the media. They have allowed it to slide because it suits their agenda.

If ME is a psychiatric illness, how come postmortem tissue and organ donation is now banned in the UK for ME patients?:

So the story appears to be, simultaneously, that ME is nothing to worry about AND subject to the official secrets act; that ME is not caused by a virus AND we cannot donate due to infection worries; that ME is a neurological illness AND the only treatment allowed is psychiatric rehabilitation, and that the scientific communication needs to be fair and accurate AND the communication with the media can say anything without substantiation, the media almost never checks the facts.